Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

描述(由申请者提供)：我们的长期目标是改善儿科肝移植受者的结果，以指导与以下相关的临床决策 一般的免疫抑制管理和特定的免疫抑制最小化和/或停药。2007年，由美国国立卫生研究院主办的一次关于儿童肝移植长期结果的共识会议得出结论：(1)长期免疫抑制会导致大量非免疫性和免疫相关的并发症，(2)识别告知免疫耐受机制的生物标志物将降低并发症的风险，并导致干预研究个体化、最小化和/或撤销。 免疫抑制。共识会议的结论与NIAID在移植免疫学方面的使命高度一致，即“进行临床试验，评估包括耐受性、抗炎和免疫调节策略在内的治疗和预防免疫介导性疾病的方法，并探索这些方法的作用机制。为了直接应对共识会议和NIAID提出的挑战，我们将进行一项多中心、单臂、前瞻性、纵向研究，以检验确定的儿科肝移植受者子集可以安全和持久地退出免疫抑制的假设(目标1)。主要终点将是手术耐受的参与者的比例，定义为那些在最后一次免疫抑制剂量后12个月通过肝脏活检和肝脏测试评估成功退出免疫抑制并维持正常同种异体移植状态的人。我们将进行广泛的转化性研究，让免疫耐受网络内外的研究团队参与进来，其目标是识别和验证预测操作耐受性的跨平台生物标记物(目标2)本研究提供了一种创新和全面的方法，将临床专家、移植病理学领域的领导者和移植免疫学领域的领导者聚集在一起，以解决关键的知识差距。这项研究的预期结果将是确定手术耐受的临床表型，这将使我们能够派生和验证交叉 平台-临床、组织学、转录和/或免疫学-生物标志物预测手术耐受性，并在这样做时，显著改变稳定的儿科肝移植的长期免疫抑制管理。

DESCRIPTION (provided by applicant): Our long-term objective is to improve outcomes for pediatric liver transplant recipients with discoveries to guide clinical decision-making related to immunosuppression management in general and immunosuppression minimization and/or withdrawal in specific. In 2007, an NIH-sponsored consensus conference on long-term outcomes in pediatric liver transplantation concluded that (1) long-term immunosuppression precipitates substantial non-immune and immune-related complications and that (2) identification of biomarkers that inform immunologic mechanisms of tolerance would lessen the risk for complications and lead to intervention studies to individualize, minimize, and/or withdraw immunosuppression. The conclusion of the consensus conference is strongly aligned with the NIAID mission in transplant immunology to "conduct clinical trials to evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases and to explore the mechanisms of action of such approaches. To directly address the challenges put forth at the consensus conference and by NIAID, we will conduct a multi-center, single arm, prospective, longitudinal study to test the hypothesis that a defined subset of pediatric liver transplant recipients can safely and durably withdraw from immunosuppression (Aim 1). The primary endpoint will be the proportion of participants who are operationally tolerant, defined as those who successfully withdraw from immunosuppression and maintain normal allograft status, assessed by liver biopsy and liver tests, 12 months after the last immunosuppression dose. We will conduct an extensive battery of translational studies, engaging research teams within and outside the Immune Tolerance Network, the goal of which is to identify and validate a cross- platform biomarker predictive of operational tolerance (Aim 2) The current study provides an innovative and comprehensive approach, bringing together clinical experts, leaders in transplant pathology and leaders in transplant immunology to address critical gaps in knowledge. The expected outcome of the study will be the identification of a clinical phenotype of operational tolerance that will enable us to derive and validate a cross platform - clinical, histological, transcriptional, and/or immunologic - biomarker predictive of operational tolerance, and in doing so, substantially alter the long-term immunosuppression management of stable pediatric liver transplantation.